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Human epidermal growth factor receptor-3 expression is regulated at transcriptional level in breast cancer settings by junctional adhesion molecule-a via a pathway involving beta-catenin and foxa1

Cruz, Rodrigo G.B. ; Madden, Stephen F. ; Richards, Cathy E. ; Vellanki, Sri Harikrishna ; Jahns, Hanne ; Hudson, Lance ; Fay, Joanna ; O’farrell, Naoimh ; Sheehan, Katherine and Jirström, Karin LU orcid , et al. (2021) In Cancers 13(4).
Abstract

The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between... (More)

The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anti-HER2 therapies, Breast cancer, Drug resistance, FOXA1, HER2, HER2-targeted therapies, HER3, JAM-A, Tight junction, Transcription factor, β-catenin
in
Cancers
volume
13
issue
4
article number
871
pages
25 pages
publisher
MDPI AG
external identifiers
  • scopus:85100940683
  • pmid:33669586
ISSN
2072-6694
DOI
10.3390/cancers13040871
language
English
LU publication?
yes
id
29b63776-75b3-4142-bc24-f80d87a3e220
date added to LUP
2021-03-02 07:45:00
date last changed
2024-04-18 02:32:28
@article{29b63776-75b3-4142-bc24-f80d87a3e220,
  abstract     = {{<p>The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.</p>}},
  author       = {{Cruz, Rodrigo G.B. and Madden, Stephen F. and Richards, Cathy E. and Vellanki, Sri Harikrishna and Jahns, Hanne and Hudson, Lance and Fay, Joanna and O’farrell, Naoimh and Sheehan, Katherine and Jirström, Karin and Brennan, Kieran and Hopkins, Ann M.}},
  issn         = {{2072-6694}},
  keywords     = {{Anti-HER2 therapies; Breast cancer; Drug resistance; FOXA1; HER2; HER2-targeted therapies; HER3; JAM-A; Tight junction; Transcription factor; β-catenin}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Human epidermal growth factor receptor-3 expression is regulated at transcriptional level in breast cancer settings by junctional adhesion molecule-a via a pathway involving beta-catenin and foxa1}},
  url          = {{http://dx.doi.org/10.3390/cancers13040871}},
  doi          = {{10.3390/cancers13040871}},
  volume       = {{13}},
  year         = {{2021}},
}